2-mercapto-3-amino-3,6-dihydro-pyrimidines



Patented Dec. 26, 1950 2-MERCAPTO-3-AMINO-3,6-DIHYDRO- PYRIMIDINES RogerA. Mathes and Floyd D. Stewart, Akron,

Ohio, assignors to The B. F. Goodrich Company, New York, N. Y., acorporation of New York No Drawing. Application September 13, 1949,

Serial No. 115,557

7 Claims. (01. 260-256.4)

This invention relates to new and useful organic compounds and pertainsparticularly to 2- mercapto-3,6-dihydropyrimidines having aminosubstituents in the 3-position and to a method for preparing these newcompounds. The compounds of this invention are 2-mercapto3-amino-3,G-dihydropyrimidines having the formula:

where R1, R2, R3, R and Rs are hydrogen or hydrocarbon radicals and R4is a hydrocarbon radical. They are useful as intermediates in thepreparation of medicinals, for example, in the synthesis of certainsulfa drugs. Other uses 'of these compounds as intermediates in thesynthesis of organic chemical compounds will be apwhere R5 and Re arehydrogen or hydrocarbon radicals, with a ketone having a hydrogen atomin the alpha position and a thiocyano group in the beta position to theketo group and being otherwise composed exclusively of carbon andhydrogen atoms (such ketones being hereinafter referred to asbeta-thiocyano ketones). During the reaction, water is split out, ringclosure occurs, the mercapto amino pyrimidine product ypirecziipitates,andis easily obtained in "excellent following generic equation;

The above reaction may be repres'entedby 1 I forthabovewherein each ofR1, R2 and Re is hydro- N=o-1lr-N-R,

AH Rs Z-mereaptoIi-amlnodihydropyrimidine where R1, R2. R3, R4,R5 and Rshave the significance as stated above.

Any desired beta-thiocyano ketone having the formula as represented inthe above equation may be used to prepare the compounds of thisinvention by the method of this invention. Thus, any or all of R1, R2and R3 may be hydrogen orany hydrocarbon radical including alkyl,alkenyl, cycloalkyl, aryl, aralkyl and alkaryl radicals as well as otherradicals composed of carbon and hydrogen. Similarly, R4 may be anyofthese hydrocarbon radicals. Beta-thiocyano ketones of this type may beprepared by the reaction of an unsaturatedketone having an olefinicdouble bond in the alpha-beta position with respect to the keto group,with nascent thiocyanic acid formed by the interaction of anon-oxidizing mineral acid, such as dilute sulfuric acid or hydrochloricacid, with ammonium thiocyanate or an alkali metal thiocyanate. Forexample, when such alpha-beta unsaturated ketones as mesityl oxide,phorone. butylidene acetone, heptylidene acetone,5-methy1-4-heptene-one-3, 5-ethyl-3-heptene-one-2, 5-

ethyl-3-nonene-one-2, 3-methyl-4-ethyl-3l-hexene-one-2, vinyl methylketone, vinyl ethyl ketone, acrylophenone, phenyl vinyl ketone,chalcone, acrylonaphthone, benzilidene acetone, 4-phenyl-3-butene-onee2, styryl n-hexyl ketone among others are reactedwith thiocyanic acid, the I-ISCN adds to the double bond of thesealphabeta unsaturated ketones. The resulting products are thebeta-thiocyano ketones which arethe reactants employed in preparing the2-mercapto-3- ,aininodihydropyrimidines of this invention. The preferredbeta-thiocyano, ketones for use in this invention are those whichpossess the formula set gen or an alkyl radical containing from 1 to 6carbon atoms and R4 is a similar alkyl radical. A typical beta-thiocyanoketone is 4-methyl 4- thiocyanopentan-Z-one prepared by the addition ofHSCN to mesityl oxide.

The material to be reacted with the beta-thiccyano ketone according tothis invention may be hydrazine or any of the hydrocarbon substitutedhydrazines represented by the generic formula hereinbefore set forth.For example, this includes such hydrazines as l-ethyl hydrazine,lemethyl hydrazine, l-propylhydrazine, 1-isopropylhydra-.- zine, l-butylhydrazine, l-isobutyl hydrazine, 1- sec-butyl hydrazine, 1-amylhydrazine, 1,1-diethyl hydrazine, 1,1-dimethyl hydrazine,1,1-diisopropyl hydrazine, l-ethyl 1'-propyl-'hydrazi e,v

l-cyclohexyl hydrazine, 1,1-dicyclohexyl hydrazine,l-methyll-cyclohexyl; hydrazine, orthomethyl cyclohexyl) hydrazine,lrphenyl hydra.- zine, l-xylyl hydrazine, 1,1'-dipheny1 hydrazine,l-(alpha naphthyl) hydrazine, l-(beta-naphthyl) hydrazine, l-(ortho,meta or. paratolyl). hydrazine, l-phenyl l-para tolyl hydrazine,l-methyl;1.-. phenyl hydrazine, l-ethyl l-phenyl hydrazine, 1- isoamyl1-phenyl hydrazine, l-isobutyll-phenyl hydrazine, 1-(2,3-dimethylphenyl) hydrazine, l- (2,5-dimethyl phenyl) hydrazine, l-benzyl- 1-(beta naphthyl) hydrazine, l-benzyl, hydrazine, l-benzylphenylhydrazine,I-benzyl phenyl'ghydrazine, l-benzyl l-(ortho, meta or para tolyl)hydrazine, l-(butyl phenyl):- hydrazine, 1-cyclo-. hexyl l-phenylhydrazine, l-cyclohexyl l-(ortho, meta or para:,tolyl,) hydrazine,1,1-dibenzyl hydrazine, -(ortho-ethyl phenyl) hydrazine, 1 hexylL-phenyl hydrazine, l-(para-methyl butyl phenyl) hydrazine,1-(para-3-methyl cyclohexyl phenyl) hydrazine, ,l-methyl 1-(methylcyclohexyl phenyl): hydrazine; l-methyl l-phenyl hydra-Zine,-,1-,;l .(2, 3-na-phthyl) -bis (triphenyl. methyl) hysdrazine,l-phenethyl-l-phenyl; hydrazine, 1.- phenyla 1.-prpy1 hydrazine, 1.-(triphenyl, methyl) hydrazine, among others.- asreactants:

In. carrying out. the preparation of 2mer.-'-capto..-3-amin0-3,6rdihydropyrimidines. the reactants arebroughttogether.- in any desired manner. Breferably the reactants .arestiredtogather. inthe. presence of. an inert reaction; dill): ent. Suchsolvents and-diluentsas water, ether-,- alcohol, benzene, hexene amongothers may be used. It is. not necessary. to employ-a reaction diluent.fon the desired reaction will take place; when the reactants are merelycombined and; heated as, herein described; But the. use of; a diluent,or. solvent facilitates proce sing, and; benceis desirable.

In. eneraL, heating the reaction; mixture; to; a; is

temperature of about 1.00 C.,in-.n1ostease desirable.

temperature inthe range of 50 C. to 100- Crwill giye thebestresults.Butthe reactionwillbegin,

atroom temperature, or below with a spontaneous rise-v in temperaturebecause. of the exothermic. nature of. the reaction. The. pressure atwhichv the reaction is carried. outmay bevaried as de--sired,,but-,..ingeneral, it will be. foundithatthe reaction is most.conveniently. carried outv at. at.

mosphericpressure. In this case, standard acid.- resistant. reaction.equipment isused.

It is alsopreferred tocarry out .thereaction in. an; acidic, reactionmedium. This. may be, accomplished by, adding to thereaction mixture.2..

When. the reaction is. carried out; at:v atmospheric. pressuremaintaining the reaction;

4 1 conditions, the reaction and the subsequent ring closure takes placemore rapidly than when the reaction medium is neutral or basic. It isnot critical that the reaction medium be acidic for the reaction andring closure will take place in a neutral medium. When crudebeta-thiocyano ketone is obtained by the reaction hereinbeforedescribed, it is suificiently acid so that the addition of an acid oracidic material is not necessary to increase the rate of reaction andring closure, Hence,.purified beta-cyanoiretone, one which hasbeenwashed with'water to remove byproduct salts and residual acid, is notsufficiently acidic to cause the reaction to proceed at the mostdesirable rate.

The following specific examples are merely illustrative of our inventionand are not intended tobe a limitation thereon. The precise proportions.in; the. examples are not critical and the amounts ofrthe reactantsemployed may be varied in keeping with-the best operational practices.

. In. each of the examples the parts are by weight.

EXAMPLE I A. mixture consisting of 39.3 parts of washed and purified4-methyl-4-thiocyano-pentan-2- one,,2 parts of dilute (0.01 molar)sulfuriciacid and 50 parts-of. water. were placed in an acid resistantreaction vessel. While stirring this mix.- ture, an .,aqueous solutioncontaining 12.69 parts of unsubstituted hydrazine monohydrate and 50parts ofwater. was slowly added, to the mixture. The, temperature. ofthe reaction. mixture, rose from room temperature to about 56 C. The.re.- action mixture was then heated to C. and a White precipitateformed. After cooling the resulting slurry to room temperature, theprecipitate was recovered by filtration and dried. In this manner 34parts, an.85% yield, of a white solid were recovered: Afterrecrystallizing the solid from ethanol, the purified product had amelting point of.-209. C. to 210 C. Thispurified productwas analyzed forcarbon, hydrogen, ni:- trogen. and sulfur. The percentage composition,as determined by analysis agreed closely withthe percentage compositioncalculated for the: desired product, 2 mercapto --3-amino.-4,6,6-tri.-methyl+3,,6.-dihydropyrimidine..

Percent composition of the product Calculated By Analysis H 7. 65, H7.70 N 24.54 N 24.57' Si 18. 72 S 18:65:.

Hence, the above product was 2-mercapto-3 amino 4,6,6 trimethyl-3,6.-dihydropyrimidine which has the formula:

iethiocyano-pentan-2-one' (crude) and 1251parts. of water was; stirredwhile 29.7 parts ofphenyl hydrazine were slowly added and" the reactiontemperature'rose from about'25" C. to 48 C. The; stirring of the mixturewas continued whilethes reactionmixture was heated to; and maintained ata temperature between C. and 909013011 22 8 hours. During this time aviscous oily material formed which solidified to a resinous substanceafter it was recovered from the reaction medium and allowed to cool. Ayield of 95% of this resiassume Hence. the product was2-mercapto-3-anilino- 4-,6,6-trimethy1-3.fi-dihydropyrimidine which. hasthe formula:

nous material was recovered. After recrystal- 5 I lizing the productfrom benzene, the purified N=C product had a melting point of 170-171 C.and A had the following chemical composition Which SE a agrees with thepercentage composition for the EXAMPLES 111 TO IX gfgg i gfg g a i' g im The examples which follow illustrate the use y y P of beta-thiocyanoketones other than 4-methy1- Percentage composition4-thiocyanopentan-2-one in preparing these 3- amino substitutedZ-mercaptopyrirnidines. In 15 each of these examples hydrazine is usedas a Calculated gg reactant with these other thiocyano ketones in orderto simplify the illustrations. It will be un- C 12 C 63 33 derstood thatany of the other hydrazines here- 1%.?) g :9 inbefore set forth can alsobe used. The reactants used and the products obtained are follows:

Example Beta-Thiocyano Ketone Used Product all III (C|H|)r-7CHCHCHr-CCH|(C:Hs)rCH(JCH=C-OH SCN N= c--NNH-| Mthyl-Mhiocyanohepteu-2-one SH (From5-ethyl-3-heptene-2-one-l-HSON)2-mercapto-3-amino-Lmethyl-6(i-ethyl-propyl)- dihydropyrimidine CzHs 1vc.1r.-0H-cHcHr-0-cm CAHFCH'fCH-CH=(IICHI 1H5 SGN N=('}N-NE1ii-ethyl-kthiocyanononau-tone 8H (From iS-ethyi-B-nonene-Z-one +HS 0N)2-mercapto-3-amino-4-methyl-6(l-ethyl-amyD- dihydropyrimidine u vCsHu-CH-GHr-C,GH; C;Hn-?HCH=?-CH. BCN N=( J---N-NH,4-thiocyanononan-2-one SH (From 3-nonene-2-one-i-HSCN)z-mercapto-3-amino4-methyl-6-amyidihydropyrimidine n VI.CaHr-CH-CHa-C-CH; Cafir-CH-CH=COHn ON N=C-NNH| kthiocyeno-heptan-z-one H(From butylldene ecetone-l-HSCN) z-mercapto-3-amino-4-methyi-6-propyldihydropyrimidine 11 VII........ CHg-CHg-G-CH: Ha(|!-CH=(|JOH; sGN N=rJ--N--NH| 4-thioeyeno-butan-2-one SH (From vinyl methyl ketone-i-HSCN) Vz-mereapto-a-amino-4-methyl-dihydropyrimidine i em-em-o-cm. GHr-CH=C-O;H

ON N=C N-NH1 fi-thioeyano-heptan-ii-one K (From vinyl ethylketone-l-HSON) mnemonic-34mlno-i-ethyl-dihydropyrlmidine if n:(fH-CHPG-CAH| GoH-cn=o-c.m 8 UN N=(I'J-N-NHi(fi-phenyl-i-thlooyanoethyi) butyl ketons SH (From styryl n-butylketone+HSCN) z-mercapto-3-amino+n-butyl-6-phenyldihydropyrimidine Amissens Havmg disclosed "our invention by way as:

specific-examples -Which "are intended" merely to be illustrative of ourprocess and the products obtained thereby :and which are not to beconstrued as..1imitationsi thereon, We do not desire nor intend tolimit. ourselves solely thereto, for it will be apparent to thoseskilled in the art that the proportions of the materials utilized, andthe time and temperature of reaction may be evaried and *other materialshaving equivalent chemical and physical properties may be em- .ployed,I=if desired, without "departing from the spirit and scope of ourinvention as defined in .the" appended claims.

We claim:

7 :1. A '2-mercapto-3 amino 3,6-dihydropyrimi- .dine having the formulawhere R1, R2, R3, R and Rs are members of' the "class consisting 'ofhydrogen and saturated aliphatic and aromatic hydrocarbon radicals andR4 is a hydrocarbon radical selected from l the class consisting ofsaturated aliphatic hydrocarbon and aromatic hydrocarbon radicals.

-2. 2 mercapto 3 amino-4,6,6-trimethy1 3,6-

3. Z-mercapto 3 anilino-4.6,6-trimethy1-3,6- dihydropyrimidine havingthe formula ('CH3)-CH-CH=CCH3 4. The process which comprises reacting abetathiocyano ketone of the formula wherein R5 and Rs are membersof theclass consisting of hydrogen and saturated aliphatic hydrocarbon andaromatic hydrocarbon radicals, thereby to produc'e'a compound'of theformula H Re wherein R1, R2, R3, B5 and R6 have the same meaning as setforth hereinabove.

5. The process of claim 4 wherein the reaction iseffecte'diin an acidicaqueous medium.

6. The process of preparing 2-mercapto-3- amino 4,6,6 trimethyl 3,6dihydropyrimidine which comprises reactingl-methyl-l-thiocyanopentan-2-one with unsubstituted hydrazine.

7. The process of preparing 2-mercapto-3- anilino 4,6,6-trimethyl 3,6dihydropyrimidine which comprises reacting4-methyl-4-thiocyanopentan-Z-one with phenyl hydrazine.

ROGER A. MATHES. FLOYD D. STEWART.

No: references cited.

1. A 2-MERCAPTO-3-AMINO-3,6-DIHYDROPYRIMIDINE HAVING THE FORMULA